We study the genetic basis of cardiovascular traits and disease, follow up genetic leads to identify unsuspected mechanisms, and test the impact of genetics on response to drugs and environment. Continue Reading →

We screen the genome in hundreds of thousands of study participants to identify chromosomal regions that harbor genes previously unsuspected to cause human disease. Because there are many genetic variants in these chromosomal regions, we perform saturation genotyping and sequencing to narrow down the causal variant. To better understand the impact of these genes in people, we follow up these exciting leads with high-resolution phenotyping of individuals selected on the basis of genotype in hospital-based trials. We have also created cellular and animal models targeting these genes to mimic human disease.

We have focused on genes involved in beneficial or detrimental responses to cardiovascular disease and probed their effects through perturbational experiments in humans, the ultimate model organism. Assessment of the impact of high sodium diet, intravenous saline challenge, inhalation of nitric oxide, administration of cardiovascular drugs are just some of the tools we employ to understand the interaction of genes, environment and drug exposure.

Our genetic studies have established definitively that specific pathways have previously unrecognized influences on human disease, such as calcium cycling on myocardial repolarization or natriuretic peptide or nitric oxide production on blood pressure regulation. We are characterizing transgenic and knockout mice as well as individual human cardiomyocytes to better understand the molecular mechanisms underpinning these pathways. We have identified novel molecular mechanisms that regulate these pathways which can potentially be exploited to treat or prevent cardiovascular disease.